: Our collaborative effort will be aimed at combining cellular and molecular approaches to study the factors that are required for the optimum development of long-lasting T cell memory to influenza virus and M. tuberculosis. Induction of such memory is the key goal of vaccination, but the pathways leading to and factors regulating memory development are poorly understood. Knowledge of the basic processes involved will yield important insights that can be exploited therapeutically and used to increase the efficacy of immunization. Disease from influenza infection ranges from mild to lethal, depending on the level of strain-specific antibody protection afforded by prior exposure to virus. Devastating epidemics have occurred when new viral strains have emerged carrying new hemagglutinin proteins distinct from those to which the population has been exposed. Such strains could also be produced by genetic engineering. Fortunately, T cell responses are not restricted to the variable epitopes and a vaccine strategy focusing on T cell immunity might provide protection to all or most potential strains and/or augment host responses sufficiently to prevent the worst consequences of a pandemic. Tuberculosis is one of the leading causes of morbidity and mortality in the world and is the leading cause of death as a result of an infectious agent. Although drug treatment is available its long duration leads to non-compliance and the subsequent generation of drug resistant strains. For the past 80 years an attenuated vaccine strain has been available however it is of variable efficacy and its use within a population fails to result in eradication of disease. Our studies will identify the kinds of memory CD4 and CD8 T cells immunity required for protection and determine factors that regulate the generation and persistence of those cells. Projects: 1. Regulation of CD4 Memory Cell Development and Persistence (Swain) will identify memory CD4 subsets in response to influenza, determine which are protective, how protective memory is generated and what regulates persistence. 2. Characterization of Influenza-Specific CD8 Memory (Dutton) will ask similar question for protective CD8 memory in influenza. Together Projects 1 and 2 will compare CD4 Vs CD8 immunity to influenza. 3. Regulation of Memory T Cell Recruitment and Responses in the Lung. (Bradley) will determine the mechanisms, which determine the recruitment of CD4 and CD8 T cells to the lung following influenza infection and will determine the responses of these cells in the lung. 4. Expression of T cell memory in the TB infected lung. (Cooper) will determine how memory responses to TB are induced, how they are recruited to the lung and whether they provide long-term protection against pulmonary TB.